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This Article Full Text (PDF) All Versions of this Article: 298/3/G419    most recent ajpgi.00362.2009v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Shang, Q. Articles by Xu, G. PubMed PubMed Citation Articles by Shang, Q. Articles by Xu, G.

Research Article

Colesevelam improves insulin resistance in a diet-induced obesity (F-DIO) rat model by increasing the release of GLP-1

¹ UMD-New Jersey Medical School ² VA Medical Center, East Orange ³ University of Copenhagen ⁴ UMDNJ-New Jersey Medical School ⁵ VA Medical Center of East Orange and University of Medicine and Dentistry of New Jersey

Submitted September 4, 2009 ; revision received December 24, 2009 ; accepted in final form December 24, 2009

Bile acid sequestrants have been shown to lower glucose levels in patients with type 2 diabetes. To investigate how Colesevelam HCl improves hyperglycemia, studies were conducted in F-DIO rats which develop insulin-resistance when fed a high-energy (high fat/high sucrose) diet (HE). The rats were fed HE (HE); HE+2% colesevelam (CL); HE+0.02% SC-435, an ASBT inhibitor (SC); and regular chow (controls). After 4 weeks of treatment, both in HE and SC+HE groups, plasma glucose and insulin levels remained elevated compared to baseline values throughout an oral glucose tolerance test (OGTT). In contrast, in the CL+HE group, plasma glucose levels returned to baseline by the end of the test and insulin peaked in 15-30 min then returned to baseline. Colesevelam induced release of GLP-1 as the area under the curve (AUC) of plasma total GLP-1in the CL+HE group was significantly greater than the HE during the OGTT. Bile acid concentrations in the portal blood did not decrease in the HE group but declined significantly both in CL+HE and SC+HE groups with reduced FXR activation as compared to controls. Conclusion: Colesevelam reduces plasma glucose levels by improving insulin-resistance in this rat model. It is unlikely that the improvement is due to decreased bile acid flux to the liver but is likely secondary to induced GLP-1 secretion which improves insulin release.

bile acid; fatty acid; intestinal absorption; CYP7A1